P53 overexpression is correlated with the presence of a mutant protein in non-small cell lung cancer. Thirty-six percent of Bronchio-alveolar lung cancer show abnormal p53 accumulation. There is evidence (both clinical and laboratory) that abnormal accumulation is not necessary for a response to the introduction of wild type p53 (wtp53). Direct transfer of the tumor suppressor gene via a recombinant adenovirus (Ad-p53) to induce apoptosis and cell death is thus a potentially attractive anti-cancer therapeutic approach for this tumor type. We have shown that re-introduction of wild-type p53 into a BAC cell line (H358 which is p53 null and does not overexpress the protein) by stable transfection results in massive apoptosis and growth inhibition. We and others have obtained similar results in this cell line by p53 delivery via recombinant adenovirus. The diffuse multilobar involvement by thin sheets of tumor cells inside the airways makes BAC frequently impossible to resect completely, and local progression is frequently the life-limiting process in this disease. It is also very resistant to chemotherapy and incurable if not completely resectable. This biology, however, makes BAC particularly amenable to gene therapeutic approaches whose vectors typically do not penetrate or diffuse into large solid tumor masses well. In particular, endobronchial delivery of recombinant wtp53 adenovirus via bronchoalveolar lavage may be a highly efficient means of gene transfer and a highly effective local therapeutic in this disease. Effective local palliation could well translate into significant clinical benefit. While BAC is only a subset of all NSCLC, the large numbers of NSCLC deaths each year and the complete lack of good therapeutic options for unresectable or recurrent BAC make the potential clinical impact of this therapy significant.